The Charot meeting has now kicked off and after the first key talks. I guess I am currently left confused, it’s the T cells, it’s the B cells, its CD8 T cells, it’s, it’s, it’s, it’s…. as Prof Hauser said today…It’s all unknown how B cell therapies work”. It’s all of them. So lots to do.
The cells are all involved, but I am not sure the dots will be linked, as seems to be the scientific way these days. I’ll have a go.
Alex Prat has talked about an adhesion molecule that is expressed on B cells that have migrated into the brain and this is called ALCAM. Activated leucocyte adhesion molecule. Alex showed that if you look at the cell types in MS that express ALCAM, it is the memory B cell subsets. So there you have it again, the memory B cell is the dominant B cell in MS (Join the dots)
However, in one talk the B cells were the major cell subtype in cortical lesions (Alex Prat) in another, it was the minor population (Hans Lassmann) and the chair did not see there difference in the talks……Maybe they remember…It’s All Unknown, but unless we get clarity it remains confusing.
Now BioGPS suggests that macrophages may express the highest levels of ALCAM and so maybe the main target. But use an anti-ALCAM and the implication would be that it could block memory (pro-inflammatory) B cell migration into the brain and perhaps it would not affect T cells.
What will happen in MS?. We don’t know, but we do know what will happen in EAE. Which was the last talk of the session by Dr Michel and it the subject of todays paper.
They found that B cells in the lymphoid tissues and CNS had more ALCAM on their surface and then they used a blocking ALCAM antibody in so called B cell dependent EAE (I call it suboptimal T cell-mediated disease that requires B cells (and other cells) for presenting antigen to make it develop).
It inhibits EAE. Great we say. Let’s do a clinical trial. However, someone with a more cynical eye may look at the data and say hang on, it shows it is rubbish.
What do I mean? Well give the anti-ALCAM and it blocks B cell infiltration into the CNS as it elegantly shown by trafficking live cells (below) in the box
We see the B cells are inhibited from getting into the CNS by about 40% but let’s look at the EAE (above), they give the antibody at onset and it essentially has no effect. In contrast if we looked at anti-CD44, it would inhibit cells getting into the CNS within a hours and it would block EAE development.
CD44 is involved in selective leucocyte extravasation during inflammatory central nervous system disease. Brennan FR, O’Neill JK, Allen SJ, Butter C, Nuki G, Baker D. Immunology. 1999; 98:427-35.
There seems to be a small effect in 3 days in the EAE data. Use in MS and get a bit of a relapse verses a relapse and it is still a relapse, so it would be seen to be a failure. It seems to help the animals recover abit and so I guess it helps on nerve loss.
However, when you look at how CD20 depleting antibody is believed to occur. The mousers say antigen presentation. Therefore blocking ALCAM shoould not work, but this study suggests effects influences on migration.
However, before throwing the idea away, remember in our hands CD20 B cell depletion does not do anything in established disease in mice and it does not do much in other people’s hands in EAE either. Therefore, the effects on EAE may not inform on what may occur in MS. So if you are a person who does not buy the mouse work, remember this detail.
Michel L, Grasmuck C, Charabati M, Lécuyer MA, Zandee S, Dhaeze T, Alvarez JI, Li R, Larouche S, Bourbonnière L, Moumdjian R, Bouthillier A, Lahav B, Duquette P, Bar-Or A, Gommerman JL, Peelen E, Prat A. Activated leukocyte cell adhesion molecule regulates B lymphocyte migration across central nervous system barriers. Sci Transl Med. 2019;11(518).
The presence of B lymphocyte-associated oligoclonal immunoglobulins in the cerebrospinal fluid is a classic hallmark of multiple sclerosis (MS). The clinical efficacy of anti-CD20 therapies supports a major role for B lymphocytes in MS development. Although activated oligoclonal populations of pathogenic B lymphocytes are able to traffic between the peripheral circulation and the central nervous system (CNS) in patients with MS, molecular players involved in this migration have not yet been elucidated. In this study, we demonstrated that activated leukocyte cell adhesion molecule (ALCAM/CD166) identifies subsets of proinflammatory B lymphocytes and drives their transmigration across different CNS barriers in mouse and human. We also showcased that blocking ALCAM alleviated disease severity in animals affected by a B cell-dependent form of experimental autoimmune encephalomyelitis. Last, we determined that the proportion of ALCAM+ B lymphocytes was increased in the peripheral blood and within brain lesions of patients with MS. Our findings indicate that restricting access to the CNS by targeting ALCAM on pathogenic B lymphocytes might represent a promising strategy for the development of next-generation B lymphocyte-targeting therapies for the treatment of MS.